PATHOPHYSIOLOGIC MECHANISMS OF LUNG INJURY AFTER BMT

描述(改编自申请人的摘要)几乎一半的 异基因骨髓移植后发生的肺炎起源于非传染性和 被称为特发性肺炎综合征(IPS)。虽然这是一个临时的 IPS与移植物抗宿主病(GVHD)之间的关联已被 据报道，两者之间的机械性关系尚不清楚 已定义。候选人已获得初步数据，支持 这种形式的肺损伤可能代表移植物对宿主的假说 针对肺部的反应。这种反应被认为涉及一连串的反应。 炎性细胞因子可以概念化为三个不同的 台阶。在第一步中，全身照射提高了宿主的能力 在骨髓输注时刺激供者T细胞的同种异体抗原。在……里面 第二步，激活的T细胞经历自我刺激和增殖，而 它们同时通过分泌来激活肺巨噬细胞 干扰素-γ(IFNY)。在第三步中，准备好的肺巨噬细胞收到 第二种信号--内源性(肠源性内毒素)或外源性 (吸入/静脉注射毒素)-并被触发释放大量 导致肺破坏的细胞毒介质(TNFa、IL-1B、NO) 组织。这项实验计划将对肺进行更具体的观察 骨髓移植后的损害，因为它与这种细胞因子级联反应的每一步有关。vbl.使用 一种成熟的小鼠骨髓移植模型，其具体目的是：1.评估 内毒素作为第二信号在IPS发生发展中的作用 通过以下方式确定对此过程负责的炎症介质 特定的细胞因子抑制剂，以消除肺损伤。2.分析 干扰素在启动肺巨噬细胞释放促炎因子中的作用 导致肺损伤的细胞因子。3.调查 移植前全身照射(TBI)的调节作用和程度 细胞因子失调传播中的供体/宿主组织不相容 以及最终的肺部毒性。 这项建议将结合密集的实验室经验和广泛的 旨在获得基本技能的教学课程 细胞和分子生物学，并开发一种关键的方法来 移植免疫学。该项目将由Dr。 费拉拉的实验室致力于了解 移植物抗宿主病的免疫病理生理机制。由高级调查人员组成的小组 DFCI将监督该项目的进展，并提供建设性的建议 为筹备并最终过渡到《公约》地位所作的批评 一名独立的首席调查员。

DESCRIPTION (Adapted from the applicant's abstract) Almost half of the pneumonias occurring after allogeneic BMT are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). Although a temporal association between IPS and graft versus host disease (GVHD) has been reported, a mechanistic relationship between the two has not been clearly defined. The candidate has obtained preliminary data that supports the hypothesis that this form of lung injury may represent a graft versus host reaction targeting the lung. This reaction is thought to involve a cascade of inflammatory cytokines that can be conceptualized as three distinct steps. In step one, total body irradiation enhances the ability of host alloantigens to stimulate donor T cells at the time of marrow infusion. In step two, activated T cells undergo self stimulation and proliferation while they simultaneously prime pulmonary macrophages by secreting Interferon-gamma (IFNy). During step three, primed lung macrophages receive a second signal - either endogenous (gut derived endotoxin) or exogenous (inhaled/intravenous toxin) - and are triggered to release large amounts of cytotoxic mediators (TNFa, IL-1B, NO) which lead to the destruction of lung tissue. This experimental plan will take a more specific look at lung damage after BMT as it relates to each step of this cytokine cascade. Using a well established murine BMT model, the specific aims are: 1. To evaluate the role of endotoxin as a second signal in the development of IPS and identify the inflammatory mediators responsible for this process by using specific cytokine inhibitors to abrogate lung injury. 2. To analyze the role of IFNy in priming pulmonary macrophages to release proinflammatory cytokines contributing to lung damage. 3. To investigate the role of pre-transplant total body irradiation (TBI) conditioning and degree of donor/host histoincompatibility in the propagation of cytokine dysregulation and eventual pulmonary toxicity. This proposal will combine an intensive laboratory experience with a broad didactic curriculum geared toward acquiring fundamental techniques in cellular and molecular biology and developing a critical approach to transplant immunology. The program will be directly supervised by Dr. Ferrara, whose laboratory is dedicated to understanding the immunopatho-physiologic mechanisms of GVHD. A panel of senior investigators at DFCI will monitor the progress of this project and offer constructive criticism to facilitate preparation for and eventual transition to status of an independent principal investigator.